Substituted pyridazine derivatives

ABSTRACT

The present invention is directed to compounds having histamine H 3  antagonist activity, as well as methods of their use and preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 12/846,112 filed Jul. 29, 2010, which is a continuation ofInternational Application No. PCT/US2009/032187, filed Jan. 28, 2009,which claims priority to U.S. Provisional Application Ser. No.61/062,908, filed Jan. 30, 2008. The disclosures of the aforementionedapplications are incorporated herein by reference in their entiretiesfor all purposes.

TECHNICAL FIELD

The present invention is directed to compounds having histamine H₃antagonist activity, as well as methods of their use and preparation.

BACKGROUND

Histamine is a well established modulator of neuronal activity and atleast four subtypes of histamine receptors have been reported in theliterature—H₁, H₂, H₃, H₄. The histamine H₃ receptors play a key role inneurotransmission in the central nervous system. H₃ receptors arepredominately expressed in the brain, localizing to the cerebral cortex,amygdala, hippocampus, striatum, thalamus and hypothalamus and can alsobe found in the periphery (skin, lung, cardiovascular system, intestine,GI tract, etc). H₃ receptors are also localized presynaptically onhistaminergic nerve terminals and act as inhibitory autoreceptors(Alguacil and Perez-Garcia, 2003; Passani et al, 2004; Leurs at al,2005; Celanire et al, 2005; Witkin and Nelson, 2004).

When H₃ receptors are activated by histamine, histamine release isinhibited. H₃ receptors are also involved in presynaptic regulation ofthe release of acetylcholine, dopamine, GABA, glutamate and serotonin(see Repka-Ramirez, 2003; Chazot and Hann, 2001; Leurs et al, 1998). TheH₃ receptor demonstrates a high degree of constitutive or spontaneousactivity (e.g., receptor is active in the absence of agoniststimulation) in vitro and in vivo, thus, ligands to the receptor candisplay, agonist, neutral antagonist or inverse agonist effects.

The location and function of histaminergic neurons in the CNS suggeststhat compounds interacting with the H₃ receptor may have utility in anumber of therapeutic applications including narcolepsy or sleep/wakedisorders, feeding behavior, eating disorders, obesity, cognition,arousal, memory, mood disorders, mood attention alteration, attentiondeficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia,schizophrenia, pain, stress, migraine, motion sickness, depression,psychiatric disorders and epilepsy (Leurs et al, 2005; Witkin andNelson, 2004, Hancock and Fox 2004; Esbenshade et al. 2006). An H₃antagonist/inverse agonist could be important for gastrointestinaldisorders, respiratory disorders such as asthma, inflammation, andmyocardial infarction.

Thus, compounds that exhibit H₃ activity are needed.

SUMMARY

The present invention is directed to compounds of Formula I:

wherein

-   -   R¹ is H, —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁹R¹⁰, halogen, C₁₋₄        alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂ aryl, 5-10        membered heteroaryl, or 3-10 membered heterocycloalkyl, wherein        each of said C₁₋₄ alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂        aryl, 5-10 membered heteroaryl, and 3-10 membered        heterocycloalkyl is optionally substituted by 1, 2, or 3 R¹¹.    -   R² and R³ are independently H or C₁₋₄ alkyl; or R² and R³ are        taken together to form a C₄₋₁₀ cycloalkyl or phenyl, wherein        each of said C₄₋₁₀ cycloalkyl and phenyl is optionally        substituted by 1, 2, or 3 halogen or C₁₋₄ alkyl;    -   each R⁴ is independently H or C₁₋₄ alkyl or OH;    -   each R⁵ is independently C₁₋₄ alkyl, or hydroxyalkyl;    -   each R⁶ is independently halogen, C₁₋₄ haloalkyl, —OH, C₁₋₄        alkyl, —O—C₁₋₄ alkyl, —NR⁹R¹⁰, or CN;    -   R⁷ is C₁₋₄ alkyl, C₄₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        C₆₋₁₂ aryl, C₆₋₁₂ arylC₁₋₆alkyl, 5-10 membered heteroarylalkyl,        or a 3-10 membered heterocycloalkyl;    -   R⁹ and R¹⁰ are independently H, C₁₋₄ alkyl, or arylalkyl;        each R¹¹ is halogen, —OH, —OC₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄        haloalkyl, or —CN.    -   X is O or S;    -   m is 2, 3, 4, 5, or 6;    -   n is 0, 1, or 2;    -   y is 0, 1, 2, 3, or 4;    -   z is 0, 1, 2, 3, or 4;        and the stereoisomers and pharmaceutically acceptable salts        thereof.

Methods of making the compounds of Formula I are also described, as wellas their pharmaceutical uses, in particular, as H₃ antagonist/inverseagonists.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present application describes compounds according to Formula I andFormula IA, pharmaceutical compositions comprising at least one compoundaccording to Formula I or Formula IA and optionally one or moreadditional therapeutic agents, and methods of treatment using thecompounds according to Formula I or Formula IA both alone and incombination with one or more additional therapeutic agents, includingall prodrugs, solvates, pharmaceutically acceptable salts andstereoisomers.

-   -   Preferred embodiments of the present invention are directed to        compounds of Formula I:

wherein

-   -   R¹ is H, —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁹R¹⁰, halogen, C₁₋₄        alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂ aryl, 5-10        membered heteroaryl, or 3-10 membered heterocycloalkyl, wherein        each of said C₁₋₄ alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂        aryl, 5-10 membered heteroaryl, and 3-10 membered        heterocycloalkyl is optionally substituted by 1, 2, or 3 R¹¹.    -   R² and R³ are independently H or C₁₋₄ alkyl; or R² and R³ are        taken together to form a C₄₋₁₀ cycloalkyl or phenyl, wherein        each of said C₄₋₁₀ cycloalkyl and phenyl is optionally        substituted by 1, 2, or 3 halogen or C₁₋₄ alkyl;    -   each R⁴ is independently H or C₁₋₄ alkyl or OH;    -   each R⁵ is independently C₁₋₄ alkyl, or hydroxyalkyl;    -   each R⁶ is independently halogen, C₁₋₄ haloalkyl, —OH, C₁₋₄        alkyl, —O—C₁₋₄ alkyl, —NR⁹R¹⁰, or CN;    -   R⁷ is C₁₋₄ alkyl, C₄₋₁₀ cycloalkyl, 5-10 membered heteroaryl,        C₆₋₁₂ aryl, C₆₋₁₂ arylC₁₋₆alkyl, 5-10 membered heteroarylalkyl,        or a 3-10 membered heterocycloalkyl;    -   R⁹ and R¹⁰ are independently H, C₁₋₄ alkyl, or arylalkyl;        each R¹¹ is halogen, —OH, —OC₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄        haloalkyl, or —CN.    -   X is O or S;    -   m is 2, 3, 4, 5, or 6;    -   n is 0, 1, or 2;    -   y is 0, 1, 2, 3, or 4;    -   z is 0, 1, 2, 3, or 4;        and the stereoisomers and pharmaceutically acceptable salts        thereof.

In preferred embodiments, R¹ is selected from the group consisting of H,—OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁹R¹⁰, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,aryl and heteroaryl. In other preferred embodiments, R¹ is halogen,C₁₋₄alkyl, aryl, heteroaryl, heterocycloalkyl, or —NR⁹R¹⁰. In otherembodiments, R¹ is H, halogen, or —NH₂. In still other embodiments, R¹is chloride or fluoride. In yet other embodiments, R¹ is OR⁷. Otherpreferred embodiments are those wherein R¹ is —SR⁷, —SOR⁷, or —SO₂R⁷.

In still other embodiments, R¹ is H, methyl, phenyl, pyrrolidinyl,piperidinyl, morpholinyl, thiophenyl, pyridinyl, —OC₁₋₄alkyl, —Oaryl,—OCH₂aryl, —SC₁₋₄alkyl, —SCH₂aryl, —SOCH₂aryl, —SO₂CH₂aryl, orbenzofuranyl. In other preferred embodiments, R¹ is H.

Certain preferred embodiments of the present invention include compoundswherein R⁵ is C₁₋₄ alkyl and n is 0.

In other preferred embodiments, R² is H. In still other embodiments, R³is H.

In most preferred embodiments, R², R³, R⁴ and R⁶ are each H.

In some preferred embodiments, R² and R³ are each H. In otherembodiments R² and R³ are taken together to form a C₄₋₁₀ cycloalkyl. Insome embodiments, R² and R³ are taken together to form a phenyl.

In some preferred embodiments of the present invention, each R⁴ isindependently H or methyl. In other embodiments, R⁴ is H.

In certain embodiments, each R⁵ is methyl. In certain other embodiments,each R⁶ is independently C₁₋₄alkyl.

Preferred embodiments of the present invention include those wherein mis 1, 2, or 3. Preferably, m is 3.

In other preferred embodiments, n is 0 or 1. Preferably n is 0.

In some embodiments, y is 0. In other embodiments, z is 1.

In the most preferred embodiments, X is O.

Particularly preferred compounds of the present invention include:

-   3-Chloro-6-{4-[3-((R)-2-methylpyrrolidin1-yl)propoxy]phenyl}pyridazine;-   3-Chloro-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]pyridazine;-   3-Methyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenylpyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-pyrrolidin-1-yl-pyridazine;-   4-(6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)morpholine;-   6-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazin-3-ylamine;-   Methyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)amine;-   1-(6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)piperidin-4-ol;-   3-Chloro-6-{3-methoxy-4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy}phenyl}pyridazine;-   3-Chloro-6-[3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   3-Chloro-6-[2-methyl-4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   5-(6-Chloro-pyridazin-3-yl)-2-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]benzonitrile;-   5-(6-Chloro-pyridazin-3-yl)-2-(3-piperidin-1-yl-propoxy)benzonitrile;-   1-Chloro-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-6,7-dihydro-5H-cyclopenta[d]pyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]phenyl}-6-thiophen-2-yl-pyridazine;-   1-Chloro-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7-dihydro-5H-cyclopenta[d]pyridazine;-   3-Chloro-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-diaza-tricyclo[6.2.2.0*2,7*]dodeca-2(7),3,5-triene;-   3-(5-Chloro-pyridin-3-yloxy)-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxyphenyl}pyridazine;-   3-Benzyloxy-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   3-Benzyloxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;-   3-Methoxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl-propoxy]-phenyl}pyridazine;-   3-Methoxy-6-{4-3-piperidin-1-yl-propoxy)-phenyl]pyridazine;-   3-Isopropoxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenylpyridazine;-   3-Phenoxy-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   3-(4-Fluoro-benzyloxy)-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-(4-trifluoromethyl-benzyloxy)pyridazine;-   Ethyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazin-3-yl)amine;-   Benzyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazin-3-yl)amine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl-propoxy]-phenyl}-6-methylsulfanylpyridazine;-   3-Methylsulfanyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   1-{4-[3-((R)-2-Methyl-pyrrolodin-1-yl)-propoxy]-phenyl}-4-methylsulfanyl-6,7-dihydro-5H-cyclopenta[d]pyridazine;-   3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;-   3-Benzylsulfanyl-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]pyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenylmethanesulfinyl-pyridazine;-   3-Phenylmethanesulfinyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenylmethanesulfonyl-pyridazine;-   3-Phenylmethanesulfonyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;-   1-Methoxy-4-{4-[3-((R)-2-methylpyrrolidin-1-yl)-propoxy]-phenyl}6,7-dihydro-5H-cyclopenta[d]pyridazine;-   1-Methoxy-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl-propoxy]-phenyl}phthalazine;-   3-Benzofuran-2-yl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazine;-   1-Benzylsulfanyl-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]-phenyl}-6,7-dihydro-5H-cyclopenta[d]pyridazine;-   3-Chloro-6-{4-[(S)-2-methyl-3-((R)-2-methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazine;-   3-Chloro-6-{4-[(S)-2-methyl-3-(2-methylpiperidin-1-yl)propoxy]-phenyl}pyridazine;    and-   6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}pyridazine;    and the pharmaceutically acceptable salts thereof.

Also within the scope of the invention are pharmaceutical compositionscomprising at least one compounds of Formula I and at least onepharmaceutically acceptable carrier or diluent. Other embodiments of theinvention include pharmaceutical compositions further comprising atleast one additional therapeutic agent.

Another embodiment of the present invention is directed to compounds ofFormula IA:

-   -   wherein

R¹ is selected from the group consisting of —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷,—OSO₂R⁷, —OCO₂R⁷, —OC(O)R⁷, —OP(O)R⁷R⁸, —NR⁹R¹⁰, halogen, C₁₋₄ alkyl,C₁₋₄ haloalkyl, aryl and heteroaryl;

R² and R³ are independently selected from the group consisting of H andC₁₋₄ alkyl, wherein when R² and R³ are both C₁₋₄ alkyl they may be takentogether to form a 4 to 10 membered mono- or bi-cyclic ring;

R⁴ is selected from the group consisting of H and C₁₋₄ alkyl;

R⁵ is selected from the group consisting of H and C₁₋₄ alkyl;

R⁶ is selected from the group consisting of H, C₁₋₄ alkyl, —O—C₁₋₄ alkyland CN;

R⁷ is selected from the group consisting of C₁₋₄ alkyl, arylalkyl andheteroarylalkyl;

R⁸ is selected from the group consisting of H and C₁₋₄ alkyl;

R⁹ and R¹⁰ are independently selected from the group consisting of H,C₁₋₄ alkyl, C₁₋₄ alkyl wherein one C atom has been replaced by aheteroatom selected from the group consisting of O, S and N andarylalkyl, wherein when R⁹ and R¹⁰ are both C₁₋₄ alkyl or one of R⁹ andR¹⁰ is a C₁₋₄ alkyl and the other is a C₁₋₄ alkyl wherein one C atom hasbeen replaced by a heteroatom selected from the group consisting of O, Sand N they may be taken together to form a 4 to 7 membered heterocycle;and

n is 0 or 1.

In preferred embodiments, R¹ is selected from the group consisting of—OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁹R¹⁰, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,aryl and heteroaryl. In other embodiments R⁵ is C₁₋₄ alkyl; and n is 0.In still other preferred embodiments, R², R³, R⁴ and R⁶ are H.

Also within the scope of the invention are pharmaceutical compositionscomprising at least one compounds of Formula IA and at least onepharmaceutically acceptable carrier or diluent. Other embodiments of theinvention include pharmaceutical compositions further comprising atleast one additional therapeutic agent.

Definitions

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50” includes ±10%of 50, or from 45 to 55. The phrase “from about 10 to 100” includes ±10%of 10 and ±10% of 100, or from 9 to 110.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6,etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, “substituted” refers to any one or more hydrogen atomson the indicated atom is replaced with a selected group referred toherein as a “substituent”, provided that the substituted atom's valencyis not exceeded, and that the substitution results in a stable compound.A substituted group has 1 to 5, preferably 1 to 3, and more preferably 1independently selected substituents. Preferred substituents include, butare not limited to F, Cl, Br, I, OH, OR, NH₂, NHR, NR₂, NHOH, NO₂, CN,CF₃, CF₂CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₃-C₇ cycloalkyl, heterocyclyl, C₆-C₁₀ aryl, heteroaryl, arylalkyl, ═O,C(═O)R, COOH, CO₂R, O—C(═O)R, C(═O)NRR′, NRC(═O)R′, NRCO₂R′, OC(═O)NRR′,—NRC(═O)NRR′, —NRC(═S)NRR′, and —SO₂NRR′, wherein R and R′ are eachindependently hydrogen, C₁-C₆ alkyl, or C₆-C₁₀ aryl.

As used herein, the term “alkyl” refers to a straight-chain or branchedalkyl group having 1 to 8 carbon atoms, preferably from 1 to 6, with 1to 3 more preferred. Exemplary alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms. Alkylgroups may be optionally substituted.

As used herein, the term “haloalkyl” refers to a straight-chain orbranched alkyl group having 1 to 8 carbon atoms, preferably from 1 to 6,with 1 to 3 more preferred, wherein at least one hydrogen atom has beenreplaced by a halogen atom. A designation such as “C₁-C₄ haloalkyl”refers to an haloalkyl radical containing from 1 to 4 carbon atoms.Examples of preferred haloalkyl radicals include —CH₂F, —CHF, and —CF₃.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.Alkenyl groups may be optionally substituted.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc. Alkynyl groups maybe optionally substituted.

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. Certain embodiments contain 3 to 6 carbon atoms, preferably 3 or4 carbon atoms, and other embodiments contain 5 or 6 carbon atoms. Adesignation such as “C₅-C₇ cycloalkyl” refers to a cycloalkyl radicalcontaining from 5 to 7 ring carbon atoms. Examples of cycloalkyl groupsinclude such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, pinenyl, pinanyl, and adamantanyl. Cycloalkylgroups may be optionally substituted.

As used herein, the term “aryl” refers to a substituted orunsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having6 to 12 ring carbon atoms. Examples include phenyl and naphthyl.Preferred aryl groups include unsubstituted or substituted phenyl andnaphthyl groups. Included within the definition of “aryl” are fused ringsystems, including, for example, ring systems in which an aromatic ringis fused to a cycloalkyl ring. Examples of such fused ring systemsinclude, for example, indane, indene, and tetrahydronaphthalene. Arylgroups may be optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a substituted or unsubstituted carbocyclic groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Certain embodiments include 4 to 9membered rings preferably 3 to 7 membered rings, and other embodimentsinclude 5 or 6 membered rings. The nitrogen and sulfur heteroatoms maybe optionally oxidized, and the nitrogen may be optionally substitutedin non-aromatic rings. Heterocycles are intended to include heteroaryland heterocycloalkyl groups. Heterocyclic groups may be optionallysubstituted.

As used herein, the term “heteroaryl” refers to an aromatic groupcontaining 5 to 10 ring carbon atoms in which one or more ring carbonatoms are replaced by at least one hetero atom such as —O—, —N—, or —S—.Certain embodiments include 5 or 6 membered rings. Examples ofheteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl,oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, picolinyl, indolyl,isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl,quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl,benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl,cinnolinyl, phthalazinyl, naphthyridinyl, and quinoxalinyl. Includedwithin the definition of “heteroaryl” are fused ring systems, including,for example, ring systems in which an aromatic ring is fused to aheterocycloalkyl ring. Examples of such fused ring systems include, forexample, phthalamide, phthalic anhydride, indoline, isoindoline,tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.Heteroaryl groups may be optionally substituted. In certain preferredembodiments, heteroaryl is pyridinyl, more preferably pyridine-2-yl, orthienyl

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—. Certain embodiments include 4 to 9membered rings and 3 to 10 membered rings, preferably 3 to 7, morepreferably 3 to 6 membered rings, and other embodiments include 5 or 6membered rings. Examples of heterocycloalkyl groups includepyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolinyl,pyrazolidinyl, pyrazalinyl, piperidinyl, piperazinyl,hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, pyranyl, oxazinyl,oxathiazinyl, and oxadiazinyl, preferably pyrrolidinyl, morpholinyl,piperidinyl, orazapanyl, more preferably pyrrolidinyl or piperidinyl.Heterocycloalkyl groups may be optionally substituted.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl,diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.preferably benzyl. Arylalkyl groups may be optionally substituted.

As used herein, the term “heteroarylalkyl” refers to an alkyl group thatis substituted with a heteroaryl group. Heteroarylalkyl groups may beoptionally substituted.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)-NH₂. The amino acids can be in their D, L orracemic configurations. Amino acids include naturally-occurring andnon-naturally occurring moieties. The naturally-occurring amino acidsinclude the standard 20 α-amino acids found in proteins, such asglycine, serine, tyrosine, proline, histidine, glutamine, etc.Naturally-occurring amino acids can also include non-α-amino acids (suchas β-alanine, γ-aminobutyric acid, homocysteine, etc.), rare amino acids(such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) andnon-protein amino acids (such as citrulline, ornithine, canavanine,etc.). Non-naturally occurring amino acids are well-known in the art,and include analogs of natural amino acids. See Lehninger, A. L.Biochemistry, 2^(nd) ed.; Worth Publishers: New York, 1975; 71-77, thedisclosure of which is incorporated herein by reference. Non-naturallyoccurring amino acids also include α-amino acids wherein the side chainsare replaced with synthetic derivatives. In certain embodiments,substituent groups for the compounds of the present invention includethe residue of an amino acid after removal of the hydroxyl moiety of thecarboxyl group thereof; i.e., groups of formula —C(═O)CH(sidechain)-NH₂. Representative side chains of naturally occurring andnon-naturally occurring α-amino acids include are shown below in TableA.

TABLE A H CH₃— HO—CH₂— C₆H₅—CH₂— HO—C₆H₄—CH₂—

HS—CH₂— HO₂C—CH(NH₂)—CH₂—S—S—CH₂— CH₃—CH₂— CH₃—S—CH₂—CH₂—CH₃—CH₂—S—CH₂—CH₂— HO—CH₂—CH₂— C₅H₉— C₆H₁₁— C₆H₁₁—CH₂— CH₃—CH(OH)—HO₂C—CH₂—NHC(═O)—CH₂— HO₂C—CH₂— HO₂C—CH₂—CH₂— NH₂C(═O)—CH₂—NH₂C(═O)—CH₂—CH₂— (CH₃)₂—CH— (CH₃)₂—CH—CH₂— CH₃—CH₂—CH₂—H₂N—CH₂—CH₂—CH₂— H₂N—C(═NH)—NH—CH₂—CH₂—CH₂— H₂N—C(═O)—NH—CH₂—CH₂—CH₂—CH₃—CH₂—CH(CH₃)— CH₃—CH₂—CH₂—CH₂— H₂N—CH₂—CH₂—CH₂—CH₂—

As used herein, the term “subject” or “patient” refers to a warm bloodedanimal such as a mammal, preferably a human, or a human child, which isafflicted with, or has the potential to be afflicted with one or morediseases and conditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of particular disorder. Such disorders include, but are notlimited to, those pathological and neurological disorders associatedwith the aberrant activity of the receptors described herein, whereinthe treatment or prevention comprises inhibiting, inducing, or enhancingthe activity thereof by contacting the receptor with a compound of thepresent invention.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

The term “pharmaceutically acceptable excipient,” as used herein,includes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents and thelike, acceptable for pharmaceutical use, for example, those that havebeen accorded Generally Regarded as Safe (GRAS) status by the U.S. Foodand Drug Administration. The use of such media and agents forpharmaceutical active substances is well known in the art, such as inRemington: The Science and Practice of Pharmacy, 20^(th) ed.; Gennaro,A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like. These physiologically acceptable salts are prepared bymethods known in the art, e.g., by dissolving the free amine bases withan excess of the acid in aqueous alcohol, or neutralizing a freecarboxylic acid with an alkali metal base such as a hydroxide, or withan amine

Compounds described herein throughout, can be used or prepared inalternate forms. For example, many amino-containing compounds can beused or prepared as an acid addition salt. Often such salts improveisolation and handling properties of the compound. For example,depending on the reagents, reaction conditions and the like, compoundsas described herein can be used or prepared, for example, as theirhydrochloride or tosylate salts. Isomorphic crystalline forms, allchiral and racemic forms, N-oxide, hydrates, solvates, and acid salthydrates, are also contemplated to be within the scope of the presentinvention.

Certain acidic or basic compounds of the present invention may exist aszwitterions. All forms of the compounds, including free acid, free baseand zwitterions, are contemplated to be within the scope of the presentinvention. It is well known in the art that compounds containing bothamino and carboxy groups often exist in equilibrium with theirzwitterionic forms. Thus, any of the compounds described hereinthroughout that contain, for example, both amino and carboxy groups,also include reference to their corresponding zwitterions.

As used herein, “prodrug” refers to compounds specifically designed tomaximize the amount of active species that reaches the desired site ofreaction, which are of themselves typically inactive or minimally activefor the activity desired, but through biotransformation are convertedinto biologically active metabolites.

Accordingly, prodrugs include, for example, compounds described hereinin which a hydroxy, amino, or carboxy group is bonded to any group that,when the prodrug is administered to a mammalian subject, cleaves to forma free hydroxyl, free amino, or carboxylic acid, respectively. Examplesinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups; and alkyl,cycloalkyl, aryl, and alkylaryl esters such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl,benzyl, and phenethyl esters, and the like.

Compounds described herein may contain one or more asymmetricallysubstituted carbon and/or sulfur atoms, and may be isolated in opticallyactive or racemic forms. Thus, all isomeric forms of a structure,including all stereogenic (such as enantiomeric, diastereomeric, and/ormeso forms, whether chiral or racemic), all achiral, all geometric,and/or all conformational isomeric forms are intended, unless thespecific stereochemical or other isomeric form is specifically indicatedand/or achiral. It is well known in the art how to prepare and isolatesuch isomeric forms of a structure including those having stereogeniccenters including those stereogenic forms wherein the structure ispresent in optically active form. For example, mixtures of stereoisomersmay be separated by standard techniques including, but not limited to,resolution of racemic forms, normal, reverse-phase, and chiralchromatography, preferential salt formation, recrystallization, and thelike, or by chiral synthesis either from chiral starting materials or bydeliberate synthesis of target chiral centers.

As used herein, the term “stereoisomers” refers to compounds that haveidentical chemical constitution, but differ as regards to thearrangement of the atoms or groups in space.

The terms “treatment” and “treating” as used herein include preventative(e.g., prophylactic), curative and/or palliative treatment. Also as usedherein, the terms “treatment,” “treating,” and “treat” refer toreversing, alleviating, or inhibiting the progress of the disorder orcondition to which the terms applies, or one or more symptoms of suchdisorder or condition.

When any variable occurs more than one time in any constituent or in anyformula, its definition in each occurrence is independent of itsdefinition at every other occurrence. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

It is believed the chemical formulas and names used herein correctly andaccurately reflect the underlying chemical compounds. However, thenature and value of the present invention does not depend upon thetheoretical correctness of these formulae, in whole or in part. Thus itis understood that the formulas used herein, as well as the chemicalnames attributed to the correspondingly indicated compounds, are notintended to limit the invention in any way, including restricting it toany specific tautomeric form or to any specific optical or geometricisomer, except where such stereochemistry is clearly defined.

In another aspect, the present invention is directed to pharmaceuticallyacceptable salts of the compounds described above. As used herein,“pharmaceutically acceptable salts” includes salts of compounds of thepresent invention derived from the combination of such compounds withnon-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric,hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as wellas organic acids such as acetic, citric, propionic, tartaric, glutamic,salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, andbenzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such asammonium and alkali and alkaline earth metal hydroxides, carbonates,bicarbonates, and the like, as well as salts derived from basic organicamines such as aliphatic and aromatic amines, aliphatic diamines,hydroxy alkamines, and the like. Such bases useful in preparing thesalts of this invention thus include ammonium hydroxide, potassiumcarbonate, sodium bicarbonate, calcium hydroxide, methylamine,diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and thelike.

In addition to pharmaceutically-acceptable salts, other salts areincluded in the invention. They may serve as intermediates in thepurification of the compounds, in the preparation of other salts, or inthe identification and characterization of the compounds orintermediates.

The pharmaceutically acceptable salts of compounds of the presentinvention can also exist as various solvates, such as with water,methanol, ethanol, dimethylformamide, ethyl acetate and the like.Mixtures of such solvates can also be prepared. The source of suchsolvate can be from the solvent of crystallization, inherent in thesolvent of preparation or crystallization, or adventitious to suchsolvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptableprodrugs of the compounds disclosed herein. As used herein, “prodrug” isintended to include any compounds which are converted by metabolicprocesses within the body of a subject to an active agent that has aformula within the scope of the present invention. Since prodrugs areknown to enhance numerous desirable qualities of pharmaceuticals (e.g.,solubility, bioavailability, manufacturing, etc.) the compounds of thepresent invention may be delivered in prodrug form. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.;Marcel Dekker: New York, 1992, incorporated by reference herein in itsentirety.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include both diastereomers and enantiomers. The compounds arenormally prepared as racemates and can conveniently be used as such, butindividual enantiomers can be isolated or synthesized by conventionaltechniques if so desired. Such racemates and individual enantiomers andmixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof Formula I and Formula IA may contain protecting groups. For example,the amino acid side chain substituents of the compounds of Formula I andFormula IA can be substituted with protecting groups such asbenzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred groups for protectinglactams include silyl groups such as t-butyldimethylsilyl (“TBDMS”),dimethoxybenzhydryl (“DMB”), acyl, benzyl (“Bn”), and methoxybenzylgroups. Preferred groups for protecting hydroxy groups include TBS,acyl, benzyl, benzyloxycarbonyl (“CBZ”), t-butyloxycarbonyl (“Boc”), andmethoxymethyl. Many other standard protecting groups employed by oneskilled in the art can be found in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

For therapeutic purposes, the compounds of the present invention can beadministered by any means that results in the contact of the activeagent with the agent's site of action in the body of the subject. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in combination with other therapeutic agents, suchas, for example, analgesics. The compounds employed in the methods ofthe present invention including, for example, the compounds of Formula Iand Formula IA may be administered by any means that results in thecontact of the active agents with the agents' site or site(s) of actionin the body of a patient. The compounds of the present invention arepreferably administered in therapeutically effective amounts for thetreatment of the diseases and disorders described herein to a subject inneed thereof.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, theformulation of the active agent with appropriate excipients, and theroute of administration. Typically, the compounds are administered atlower dosage levels, with a gradual increase until the desired effect isachieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A preferred daily dose for adult humans includesabout 25, 50, 100 and 200 mg, and an equivalent dose in a human child.The compounds may be administered in one or more unit dose forms. Theunit dose ranges from about 1 to about 500 mg administered one to fourtimes a day, preferably from about 10 mg to about 300 mg, two times aday. In an alternate method of describing an effective dose, an oralunit dose is one that is necessary to achieve a blood serum level ofabout 0.05 to 20 μg/ml in a subject, and preferably about 1 to 20 μg/ml.

Although the compounds of the present invention may be administered asthe pure chemicals, it is preferable to present the active ingredient asa pharmaceutical composition.

Generally speaking, therapeutic compounds of this invention may beadministered to a patient alone or in combination with apharmaceutically acceptable carrier. Accordingly, the compounds of theinvention, for example, compounds of Formula I and Formula IA, arepreferably combined with a pharmaceutical carrier selected on the basisof the chosen route of administration and standard pharmaceuticalpractice as described, for example, in Remington's PharmaceuticalSciences (Mack Publishing Co., Easton, Pa., 1980), the disclosures ofwhich are hereby incorporated herein by reference, in their entireties.The carrier(s) must be acceptable in the sense of being compatible withthe other ingredients of the composition and not deleterious to therecipient thereof. The relative proportions of active ingredient andcarrier may be determined, for example, by the solubility and chemicalnature of the compounds, chosen route of administration and standardpharmaceutical practice.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The excipients are selected onthe basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000. The compositionsmay be formulated to control and/or delay the release of the activeagent(s), as in fast-dissolve, modified-release, or sustained-releaseformulations. Such controlled-release, or extended-release compositionsmay utilize, for example biocompatible, biodegradable lactide polymers,lactide/glycolide copolymers, polyoxyethylene-polyoxypropylenecopolymers, or other solid or semisolid polymeric matrices known in theart.

The compositions can be prepared for administration by oral means;parenteral means, including intravenous, intramuscular, and subcutaneousroutes; topical or transdermal means; transmucosal means, includingrectal, vaginal, sublingual and buccal routes; ophthalmic means; orinhalation means. Preferably the compositions are prepared for oraladministration, particularly in the form of tablets, capsules or syrups;for parenteral administration, particularly in the form of liquidsolutions, suspensions or emulsions; for intranasal administration,particularly in the form of powders, nasal drops, or aerosols; or fortopical administration, such as creams, ointments, solutions,suspensions aerosols, powders and the like.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidones; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; or flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the afore listedexcipients, and may additionally contain a semi-solid or liquid carrier,such as a polyethylene glycol. The solid oral dosage forms may havecoatings of sugar, shellac, or enteric agents. Liquid preparations maybe in the form of aqueous or oily suspensions, solutions, emulsions,syrups, elixirs, etc., or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assurfactants, suspending agents, emulsifying agents, diluents, sweeteningand flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers, and the like. Theparenteral preparations can be enclosed in ampules, disposable syringesor multiple dose vials. Other potentially useful parenteral deliverysystems for the active compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

Pharmaceutical kits useful in, for example, the treatment of pain, whichcomprise a therapeutically effective amount of a compound of theinvention and/or other therapeutic compounds described herein, in one ormore sterile containers, are also within the ambit of the presentinvention. Sterilization of the container may be carried out usingconventional sterilization methodology well known to those skilled inthe art. The sterile containers of materials may comprise separatecontainers, or one or more multi-part containers, as exemplified by theUNIVIAL™ two-part container (available from Abbott Labs, Chicago, Ill.),as desired. The compound of the invention and/or other therapeuticcompound as described herein may be separate, or combined into a singledosage form as described above. Such kits may further include, ifdesired, one or more of various conventional pharmaceutical kitcomponents, such as for example, one or more pharmaceutically acceptablecarriers, additional vials for mixing the components, etc., as will bereadily apparent to those skilled in the art. Instructions, either asinserts or as labels, indicating quantities of the components to beadministered, guidelines for administration, and/or guidelines formixing the components, may also be included in the kit.

The compounds of the present invention may be used in methods to bindhistamine receptors, more preferably histamine H₃ receptors. Suchbinding may be accomplished by contacting the receptor with an effectiveamount of a compound of Formula I or Formula IA. The histamine receptorsmay be located in the central nervous system or located peripherally tothe central nervous system or in both locations. Preferably, thecontacting step conducted in an aqueous medium, preferably atphysiologically relevant ionic strength, pH, and the like.

In yet another aspect, the invention is directed to methods of bindinghistamine receptors, more preferably histamine H₃ receptors, comprisingthe step of administering to a patient in need thereof, an effectiveamount of a compound of the invention including, for example, a compoundof Formula I or Formula IA.

In certain preferred aspects, the methods comprise the step ofadministering to said patient an therapeutically effective amount of acompound of Formula.

In some preferred embodiments, the histamine receptors are H³ histaminereceptors. In certain more preferred embodiments, the compoundselectively binds H³ histamine receptors relative to H₁, H₂ and/or H₄receptors. In certain preferred embodiments, the H³ histamine receptorsare located in the central nervous system. In some other preferredembodiments, the compound of Formula I or Formula IA exhibits activitytoward the histamine receptors. In certain preferred embodiments, thebinding agonizes the activity of the cannabinoid receptors. In otherpreferred embodiments, the binding antagonizes the activity of thecannabinoid receptors, more preferably as a neutral antagonist. In stillother preferred embodiments, the binding inversely agonizes the activityof the cannabinoid receptors.

In yet other preferred embodiments, the compounds of Formula I andFormula IA thereof exhibit activity toward the histamine receptors invivo. In alternatively preferred embodiments, the compounds of Formula Iand Formula IA exhibit activity toward the histamine receptors in vitro.

In certain other preferred aspects of the invention, there are providedmethods of treating a disease, disorder or condition that may beaffected, modulated or controlled through the binding of histamine,preferably H₃ histamine receptors. More preferably these diseases,disorders, and/or conditions selected from the group consisting ofnarcolepsy or sleep/wake disorders, feeding behavior disorders, eatingdisorders, obesity, cognition disorder, arousal disorder, memorydisorder, mood disorders, mood attention alteration, attention deficithyperactivity disorder (ADHD), Alzheimer's disease/dementia,schizophrenia, pain, stress, migraine, motion sickness, depression,psychiatric disorders, epilepsy, gastrointestinal disorders, respiratorydisorders, inflammation, and myocardial infarction. In preferredembodiments, the disease or disorder is narcolepsy or sleep/wakedisorder. In other preferred embodiments, the disease or disorder isattention deficit hyperactivity disorder. In still other embodiments,the disease or disorder is a cognition disorder. The methods hereinprovided comprise administering to a subject in need of such treatment atherapeutically effective amount of a compound of the invention,preferably a compound of Formula I or Formula IA.

In certain preferred embodiments, the disorder is narcolepsy orsleep/wake disorders. Alternatively the disorder treated is attentiondeficit hyperactivity disorder.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

Methods of Preparations

The compounds of the present invention may be prepared in a number ofmethods well known to those skilled in the art, including, but notlimited to those described below, or through modifications of thesemethods by applying standard techniques known to those skilled in theart of organic synthesis. All processes disclosed in association withthe present invention are contemplated to be practiced on any scale,including milligram, gram, multigram, kilogram, multikilogram orcommercial industrial scale.

The general routes to prepare the examples shown herein are shown in theSchemes 1 to 6. The reagents and starting materials are commerciallyavailable, or readily synthesized by well-known techniques by one ofordinary skill in the arts. All substituents in the synthetic Schemes,unless otherwise indicated, are as previously defined.

A boron ether derivative of general formula X, wherein R⁶ is definedabove and R¹¹ is for example lower alkyl, is alkylated with asubstituted alkane of general formula XI, wherein R¹² and R¹³ aresuitable leaving groups such as bromine or chlorine, in the presence ofa base, such as an alkali metal carbonate or a nitrogenous base such astriethylamine, in a suitable solvent such as toluene, a dialkyl ether,p-dioxane or tetrahydrofuran. The resultant ether derivative of generalformula XII is then reacted in a nucleophilic displacement reaction,with an amine of general formula XIII, in the presence of a base and asuitable solvent, to provide a boron ether or boronic acid derivative ofgeneral formula XIV. This compound is subjected to a transition-metalcatalyzed coupling reaction with a pyridazine derivative of generalformula XV, wherein R¹, R² and R³ are as defined above, and R¹⁴ is asuitable leaving group, under conditions such as those corresponding toa Suzuki coupling reaction, in the presence of a suitable palladiumcatalyst as for example described in Cross-Coupling Reactions. APractical Guide. [In: Top. Curr. Chem., 2002; 219] Miyaura, Norio;Editor. (2002), Publisher: (Springer-Verlag, Berlin, Germany), toprovide a compound of general Formula I or Formula IA, wherein n andsubstituents R¹ to R⁶ are as defined above. An example of detailedmethodology for such reactions is illustrated in the procedure toprovide Example 1.

A boron ether or boronic acid derivative of general formula XVI, whereinR⁴ and R⁶ are as defined above, R¹¹ is for example lower alkyl orhydrogen, R¹⁵ is for example an alcohol, or another functionality thatcan readily be converted into a leaving group by standard methods, issubjected to a transition-metal catalyzed coupling reaction, with apyridazine derivative of general formula XV, wherein R¹, R² and R³ areas defined above, and R¹⁴ is a suitable leaving group. under conditionssuch as those corresponding to a Suzuki coupling reaction, in thepresence of a suitable palladium catalyst as for example described inCross-Coupling Reactions. A Practical Guide. [In: Top. Curr. Chem.,2002; 219] Miyaura, Norio; Editor. (2002), Publisher: (Springer-Verlag,Berlin, Germany), to provide a compound of general formula XVII. Thisproduct is converted into a compound of general formula XVIII, whereinR¹⁶ is a suitable leaving group, for example a mesylate, ap-toluenesulfonate or a halogen such as bromine or chlorine. Thisintermediate XVIII is converted into a compound of general Formula I orIA, wherein n and substituents R¹ to R⁶ are as described above, in anucleophilic displacement reaction, with a cyclic amine of generalformula XIII, in the presence of a base and a suitable solvent.

An example of detailed methodology for such reactions is illustrated inthe procedure to provide Example 43.

The transition-metal catalyzed coupling strategies for the synthesis ofcompounds of general formula XII or XVII illustrated in Schemes 1 and 2are characterized for example by a phenyl boronic ester or relatedfunctionality reacting for example with a halogenated pyridazinederivative in the presence of a suitable palladium-derived catalyst.Usable alternatives exist whereby a compound of formula XIX, wherein R⁴,R⁶, R¹² and R¹⁵ are as defined above, is allowed to react with apyridazine-containing boron derivative, of formula XX, wherein R¹, R²,R³ and R¹¹ are defined above, using general methods as for exampledescribed in Cross-Coupling Reactions. A Practical Guide. [In: Top.Curr. Chem., 2002; 219] Miyaura, Norio; Editor. (2002), Publisher:(Springer-Verlag, Berlin, Germany), to provide a compound of generalformula XVII, wherein substituents R¹ to R⁴, R⁶ and R¹⁵ are as describedabove. This compound of formula XVII may be converted into a compound offormula I or IA by the procedures outlined in Scheme 2.

This strategy of a reversed transition-metal catalyzed coupling strategyis further illustrated by the reaction of a phenyl ether of generalformula XXI, wherein n, R⁴, R⁵, R⁶ are defined above, and R¹⁵ is asuitable leaving group, is allowed to react with a pyridazine-containingboron derivative, of formula XX, wherein R¹, R², R³ and R¹¹ are definedabove, using general methods as for example described in Cross-CouplingReactions. A Practical Guide. [In: Top. Curr. Chem., 2002; 219] Miyaura,Norio; Editor. (2002), Publisher: (Springer-Verlag, Berlin, Germany), toprovide a compound of general Formula I or IA, wherein n andsubstituents R¹ to R⁶ are as described above.

In cases where a preformed pyridazine derivative such as XXII isavailable by the general methods described herein, wherein n,substituents R² to R⁶ are as defined above, and R¹⁵ is a suitableleaving group, a compound of Formula I or IA may be generated bynucleophilic displacement by a range of nucleophiles, such as suitablysubstituted alcohols, thiols and amines, represented by the formulaeHOR⁷, HSR⁷, HNR⁹R¹⁰ in the presence of an appropriate base.

An example of detailed methodology for such reactions is illustrated inthe procedure to provide Example 20.

In examples where the R¹ group in an example such as compound XXIII is—SOR⁷ or —SO₂R⁷, wherein R⁷, n and substituents R¹ to R⁶ are as definedabove, an oxidation reaction of a compound such as XXIV, wherein R⁷ isas defined above may be carried out by a range of oxidizing agents, suchas m-chloroperbenzoic acid, hydrogen peroxide or oxone. If the desiredR¹ group is —SOR⁷, milder conditions may be used, such as Oxone inaqueous alcohol or tetrahydrofuran, at lowered temperature.

An example of detailed methodology for such reactions is illustrated inthe procedure to provide Example 35.

A 1,4-diketone derivative of general formula XXV, wherein R², R³, R⁴ andR⁶ are as defined above, R¹⁵ is a suitable leaving group, and R¹² is forexample a hydroxyl group, is reacted with a cyclic amine of generalformula XIII, wherein n and R⁵ are as defined above, in the presence ofa base and a suitable solvent, to provide a compound of general formulaXXVI, wherein n, R², R³, R⁴, R⁵, R⁶ and R¹² are as defined above. The1,4-diketone derivative XXVI is then reacted for example with hydrazinehydrate to provide a pyridazine derivative of formula XXVII, wherein n,R², R³, R⁴, R⁵, R⁶ are as defined above. In some cases R¹⁸, which mayinitially be a hydroxyl group, will require further elaboration, forexample by chlorination, utilizing reagents such as thionyl chloride orphosphorus oxychloride, to provide examples wherein R¹⁸ is for examplehalogen. The product then represents a compound of Formula I or IA, orcan readily be elaborated into further compounds of formula I or IA bymethods described herein.

A range of further methods for conversion of 3-substitutedphenoxypropylpyrrolidine derivatives and 3-substitutedphenoxypropylpiperidine derivatives into the corresponding pyridazinederivatives are available, for example as described in standardtextbooks of heterocyclic chemistry such as Heterocyclic Chemistry,Fourth Edition. Joule, J. A.; Mills, K. (2000). Publisher: BlackwellScience Ltd., Oxford, UK.

EXAMPLES Example 13-Chloro-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]-phenyl}pyridazine

2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (CAS#269409-70-3) (10.5 g, 47 mmol) was dissolved in dry CH₃CN (200 mL) anddry, pulverized K₂CO₃ (10.4 g, 75 mmol) was introduced.1,3-dibromopropane (38.1 mL, 375 mmol) was added dropwise, and thereaction mixture was heated at 70° C. for 7 h under a nitrogenatmosphere. The cooled reaction mixture was filtered and the filtratewas evaporated to an oily residue, which was applied to a column ofsilica gel. Elution initially with hexanes, gradually increasingpolarity to a mixture of hexanes/ethyl acetate (25:1, 20:1 and 10:1) aseluent, provided the title compound (13.93 g, 86%) which crystallized onstanding to a white solid, m.p. 62-65° C.

(R)-2-Methyl-1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-pyrrolidine

2-[4-(3-Bromopropoxy)phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane(20.47 g, 60 mmol), (R)-2-methylpyrrolidine hydrochloride (7.663 g, 63mmol) and dry, pulverized K₂CO₃ (24.96 g, 180 mmol) were mixed in dryCH₃CN (650 mL). After stirring for 12 h at 78° C. under a nitrogenatmosphere, the reaction mixture was cooled and further(R)-2-methylpyrrolidine hydrochloride (10.0 g, 82 m mol) was introducedand heating at 78° C. was continued for 24 h. The reaction mixture wascooled, filtered and the filtrate was evaporated. Chromatography onsilica gel, eluting initially with CH₂Cl₂, then with a mixture ofCH₂Cl₂/EtOH/aq. NH₃ (290:10:1) and later with a (90:10:1) and (40:10:1)mixture of these solvents provided the title compound (17.44 g, 84%).The material crystallized on seeding. A sample was converted into ahydrochloride salt, m.p. 212-214° C.

3-Chloro-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}pyridazine(Example 1)

Pd(OAc)₂ trimer (2.02 g, 9.0 mmol) and Ph₃P (9.36 g, 35.6 mmol) weresuspended in anhydrous THF (300 mL) and stirred vigorously under anitrogen atmosphere for 10 min. 3,6-dichloropyridazine (26.82 g, 180mmol) was added as a solid and stirring was continued for 10 min.(R)-2-Methyl-1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propyl}-pyrrolidine(11.76 g, 34 mmol) was dissolved in a mixture of THF (200 mL) and EtOH(100 mL) and added dropwise to the reaction mixture. Saturated NaHCO₃solution (360 mL) was introduced. The reaction mixture was heated at 80°C. for 15 h, cooled and was evaporated to a residue, which was taken upin CH₂Cl₂ (300 mL) and washed with water and saturated NaHCO₃ solution.The CH₂Cl₂phase was dried (Na₂SO₄) and evaporated. The product wasobtained by ISCO chromatography on silica gel, eluting with EtOAcinitially, then with a mixture of EtOAc/CH₃OH (9:1) to provide the titlecompound (10.20 g, 90%) as a cream solid, m.p. 107-108.5° C.; ¹H NMR(CDCl₃) 1.10 (d, 3H, —CH₃), 2.99 (m, 2H, —CH₂—), 3.18 (m, 2H, —CH₂—),4.10 (m, 2H, —CH₂—), 7.04 (d, 2H, Ar—H), 7.50 (d, 1H, C—H), 7.78 (d, 1H,C—H), 7.99 (d, 2H, Ar—H) (representative signals only); HPLC retentiontime 6.893 min. (elution solvents CH₃CN w/0.1% TFA and H₂O w/0.1% TFA;column: Agilent Zorbax RX-C8 4.6 mm×150 mm w/5 μm particle size; method:10-100% CH₃CN over 20 min., 100% CH₃CN for an additional 4.5 minutes;flow rate: 1.6 mL/min; System: Agilent 1100 HPLC).

The following examples were prepared by the procedure described inExample 1, a transition-metal catalyzed coupling reaction of theappropriate 3-halo pyridazine with(R)-2-methyl-1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propyl}pyrrolidineor1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]propyl}piperidine:

TABLE I HPLC Example Melting Retention number Structure Point (° C.)Time (min.) NMR data 2

140   2.035^(a) ¹H NMR (CDCl₃) 2.45 (m, 2H, —CH₂—), 2.5 (m, 2H, —CH₂—),4.10 (m, 2H, —CH₂—), 7.04 (d, 2H, Ar—H), 7.50 (d, 1H, C—H), 7.75 (d, 1H,C—H), 8.00 (d, 2H, Ar—H) 3

n/a 4.188 ¹H NMR (CDCl₃) 1.12 (d, 3H, —CH₃), 3.01 (m, 2H, —CH₂—), 3.20(m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.02 (d, 2H, Ar—H), 7.34 (d, 1H,C—H), 7.69 (d, 1H, C—H), 8.02 (d, 2H, Ar—H) 4

158-160 7.926 ¹H NMR (CDCl₃) 1.12 (d, 3H, —CH₃), 3.03 (m, 2H, —CH₂—),3.22 (m, 2H, —CH₂—), 4.13 (m, 2H, —CH₂—), 7.07 (d, 2H, Ar—H), 7.51 (d,1H, C—H), 8.12 (d, 2H, Ar—H) 5

175-180 4.875 ¹H NMR (CDCl₃) 1.20 (d, 3H, —CH₃), 3.09 (m, 2H, —CH₂—),3.30 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 6.69 (d, 1H, C—H), 6.99 (d,2H, Ar—H), 7.58 (d, 1H, C—H), 7.92 (d, 2H, Ar—H) 6

n/a 4.332 ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 3.10 (m, 2H, —CH₂—), 3.19(m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 6.96 (d, 1H, C—H), 7.00 (d, 2H,Ar—H), 7.63 (d, 1H, C—H), 7.94 (d, 2H, Ar—H) 7

121-122 3.096 ¹H NMR (d⁶- DMSO) 1.00 (d, 3H, —CH₃), 2.91 (m, 2H, —CH₂—),3.08 (m, 2H, —CH₂—), 4.07 (m, 2H, —CH₂—), 6.81 (d, 1H, C—H), 7.01 (d,2H, Ar—H), 7.73 (d, 1H, C—H), 7.89 (d, 2H, Ar—H) 8

126-129 3.894 ¹H NMR (CDCl₃) 1.09 (d, 3H, —CH₃), 3.01 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.09 (m, 2H, —CH₂—), 6.69 (d, 1H, C—H), 6.97 (d,2H, Ar—H), 7.58 (d, 1H, C—H), 7.91 (d, 2H, Ar—H) 9

138-141 3.701 ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 6.99 (d, 1H, C—H), 7.58(d, 1H, C—H), 7.92 (d, 2H, Ar—H) 10

122  4.759^(b) ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.17 (m, 2H, —CH₂—), 7.03 (d, 1H, C—H), 7.50 (d,1H, Ar—H), 7.60 (d, 1H, C—H), 7.82 (d, 2H, Ar—H) 11

120  4.780^(b) ¹H NMR (CDCl₃) 2.40 (m, 2H, —CH₂—), 4.18 (m, 2H, —CH₂—),7.01 (d, 1H, C—H), 7.48 (d, 1H, Ar—H), 7.52 (d, 1H, Ar—H), 7.80 (d, 1H,Ar—H) 12

 85  5.007^(b) ¹H NMR (CDCl₃) 2.01 (m, 2H, —CH₂—), 2.50 (m, 2H, —CH₂—),4.10 (m, 2H, —CH₂—), 6.88 (d, 2H, C—H), 6.95 (d, 2H, Ar—H), 7.40 (d, 1H,C—H), 7.55 (s, 1H, Ar—H) 13

134-136   2.742^(c) ¹H NMR (d⁶- DMSO) 1.00 (d, 3H, —CH₃), 4.29 (m, 2H,—CH₂—), 7.45 (d, 1H, C—H), 8.04 (d, 1H, C—H), 8.40 (d, 1H, C—H),8.48-8.53 (m, 2H, Ar—H) 14

140-142   2.844^(c) ¹H NMR (CDCl₃) 2.35 (m, 4H, —CH₂—), 4.26 (m, 2H,—CH₂—), 7.20 (d, 1H, C—H), 7.60 (d, 1H, Ar—H), 7.81 (d, 1H, C—H) 8.34(d, 1H, Ar—H) 15

120   2.368^(a) ¹H NMR (CDCl₃) 3.06 (m, 2H, —CH₂—), 3.20 (m, 2H, —CH₂—),4.10 (m, 2H, —CH₂—), 7.05 (d, 2H, Ar—H), 7.80 (d, 2H, Ar—H) 16

108   2.373^(a) ¹H NMR (CDCl₃) 1.13 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.09 (m, 2H, —CH₂—), 6.72 (d, 1H, C—H), 7.00 (d,2H, Ar—H), 7.70 (d, 1H, C—H), 8.10 (d, 2H, Ar—H) 17

 65   2.364^(a) ¹H NMR (CDCl₃) 1.09 (d, 3H, —CH₃), 3.05 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.05 (d, 2H, Ar—H), 7.80 (d,2H, Ar—H) 18

132-134 9.345 ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.03 (d, 2H, Ar—H), 7.54 (d,2H, Ar—H) 19

119 8.560 ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 2.99 (m, 2H, —CH₂—), 3.20(m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.01 (d, 1H, C—H), 7.30 (d, 2H,Ar—H), 7.95 (d, 2H, Ar—H), 8.50 (d, 1H, C—H) ^(a)HPLC conditions asdescribed in Example 1, but with a gradient of 10-100% CH₃CN over 5 min^(b)HPLC conditions 10-100% CH₃CN over 10 min ^(c)HPLC conditions10-100% CH₃CN over 8 min

Example 20 3-Benzyloxy-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine

Sodium hydride (0.007 g, 0.18 mmol) was stirred in anhydrous DMF (4 mL)under a nitrogen atmosphere, and benzyl alcohol (0.016 g, 0.15 mmol) wasadded. After 15 min.,3-chloro-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]-pyridazine (0.05 g,0.15 mmol) was introduced, and the reaction mixture was stirred at roomtemperature for 5 h. The precipitate was collected by filtration, washedwith H₂O (10 mL) and dried in vacuo to provide the title compound as awhite solid (0.050 g, 83%), m.p. 138° C.; ¹H NMR (CDCl₃) 2.00 (m, 2H,—CH₂—), 2.50 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 1H, C—H),7.05 (d, 2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) HPLC retentiontime 2.612 min^(a).

Example 353-{4-[3-((R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-6-phenylmethanesulfinyl-pyridazine

3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazine(0.08 g, 0.19 mmol) was dissolved in CH₃CO₂H (3 mL) and a 50% solutionof H₂O₂ in H₂O (0.026 mL, 0.16 mmol) was introduced. The reactionmixture was stirred and monitored by LC-MS, and after 5 h was evaporatedto a residue, which was treated with H₂O (20 mL) and CH₂Cl₂ (30 mL). Theorganic layer was washed with saturated NaHCO₃ solution (20 mL),saturated brine (10 mL) and dried (MgSO₄) before being evaporated to awhite solid (0.051 g, 64%), m.p. 145° C.

Example 373-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]phenyl}-6-phenylmethanesulfonyl-pyridazine

3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazine(0.065 g, 0.15 mmol) was dissolved in CH₃CH₂OH (3 mL) and a solution of“Oxone”, potassium peroxymonosulphate (0.36 g, 0.23 mmol) in H₂O (1 mL)was introduced. The reaction mixture was stirred and monitored by LC-MS,and after 2 h was evaporated to a residue, which was treated with EtOAc(20 mL) washed with saturated NaHCO₃ solution (20 mL), saturated brine(10 mL) and dried (MgSO₄) before being evaporated to a white solid(0.028 g, 40%), m.p. 136° C.

The following examples were prepared by the procedures described inExamples 20, 35 and 37. In some cases, such as in Examples 35-38,further sulfur oxidation stages are required to prepare the compoundsdescribed, as illustrated in Examples 35 and 37.

TABLE II Exam- HPLC ple Melting Retention num- Point Time ber Structure(° C.) (min.) NMR data 21

114   2.575^(a) ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.05 (d, 1H, C—H), 7.40 (d,2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) 22

121   1.687^(a) ¹H NMR (CDCl₃) 1.12 (d, 3H, —CH₃), 2.98 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.15 (m, 2H, —CH₂—), 7.00 (d, 2H, Ar—H), 7.31 (d,1H, C—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) 23

116   1.683^(a) ¹H NMR (CDCl₃) 2.75 (m, 4H, —CH₂—), 4.10 (m, 2H, —CH₂—),7.00 (d, 1H, C—H), 7.05 (d, 2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H,Ar—H) 24

 75   2.134^(a) ¹H NMR (CDCl₃) 1.60 (d, 3H, —CH₃), 2.20 (m, 2H, —CH₂—),2.98 (m, 2H, —CH₂—), 4.11 (m, 2H, —CH₂—), 7.28 (d, 2H, Ar—H), 7.40 (d,2H, Ar—H) 25

139   2.544^(a) ¹H NMR (CDCl₃) 4.10 (m, 2H, —CH₂—), 6.98 (d, 2H, Ar—H),7.25 (d, 1H, C—H), 7.83 (d, 1H, C—H), 7.97 (d, 2H, Ar—H) 26

118   2.658^(a) ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 1H, C—H), 7.03 (d,2H, Ar—H), 7.75 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) 27

160   3.018^(a) ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 2.98 (m, 2H, —CH₂—),3.18 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 1H, C—H), 7.10 (d,2H, Ar—H), 7.85 (d, 1H, C—H), 7.95 (d, 2H, Ar—H) 28

n/a 4.509 ¹H NMR (CDCl₃) 1.37 (d, 3H, —CH₃), 3.13 (m, 2H, —CH₂—), 3.38(m, 2H, —CH₂—), 4.09 (m, 2H, —CH₂—), 6.89 (d, 1H, C—H), 6.96 (d, 2H,Ar—H), 7.62 (d, 1H, C—H), 7.77 (d, 2H, Ar—H) 29

139.5-141 6.904 ¹H NMR (CDCl₃) 1.13 (d, 3H, —CH₃), 3.01 (m, 2H, —CH₂—),3.21 (m, 2H, —CH₂—), 4.09 (m, 2H, —CH₂—), 6.69 (d, 1H, C—H), 6.97 (d,2H, Ar—H), 7.56 (d, 1H, C—H), 7.89 (d, 2H, Ar—H) 30

101   2.253^(a) ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 2.98 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 2H, Ar—H), 7.60 (d,1H, C—H), 8.00 (d, 2H, Ar—H) 31

122   1.975^(a) ¹H NMR (CDCl₃) 2.40 (m, 2H, —CH₂—), 2.61 (m, 2H, —CH₂—),4.05 (m, 2H, —CH₂—), 7.10 (d, 2H, Ar—H), 7.4 (d 1H, C—H), 7.60 (d, 1H,C—H), 8.00 (d, 2H, Ar—H) 32

n/a   1.966^(a) ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 2.89 (m, 2H, —CH₂—),3.17 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 2H, Ar—H), 7.80 (d,2H, Ar—H) 33

104   2.789^(a) ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.21 (m, 2H, —CH₂—), 4.11 (m, 2H, —CH₂—), 6.75 (d, 1H, C—H), 7.01 (d,2H, Ar—H), 7.65 (d, 1H, C—H), 8.00 (d, 2H, Ar—H) 34

144 2.822 ¹H NMR (CDCl₃) 2.05 (m, 2H, —CH₂—), 2.52 (m, 2H, —CH₂—), 4.05(m, 2H, —CH₂—), 7.00 (d, 1H, C—H), 7.30 (d, 2H, Ar—H), 7.60 (d, 1H,C—H), 8.00 (d, 2H, Ar—H) 35

145   2.238^(a) ¹H NMR (CDCl₃) 1.12 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.22 (m, 2H, —CH₂—), 4.12 (m, 2H, —CH₂—), 7.65 (d, 1H, C—H), 7.83 (d,1H, C—H), 8.09 (d, 2H, Ar—H) 36

186   2.238^(a) ¹H NMR (CDCl₃) 2.41 (m, 2H, —CH₂—), 2.50 (m, 2H, —CH₂—),4.10 (m, 2H, —CH₂—), 7.03 (d, 2H, Ar—H), 7.23 (d, 1H, C—H), 7.85 (d, 1H,C—H), 8.10 (d, 2H, Ar—H) 37

136   2.619^(a) ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 3.05 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.02 (d, 2H, Ar—H), 7.30 (d,1H, C—H), 7.85 (d, 1H, C—H), 8.15 (d, 2H, Ar—H) 38

134 6.15^(c) ¹H NMR (CDCl₃) 2.05 (m, 2H, —CH₂—), 2.525 (m, 2H, —CH₂—),4.05 (m, 2H, —CH₂—), 7.00 (d, 1H, C—H), 7.03 (d, 2H, Ar—H), 7.85 (d, 1H,C—H), 8.10 (d, 2H, Ar—H) 39

109   1.712^(a) ¹H NMR (d⁶-DMSO) 1.40 (d, 3H, —CH₃), 2.90 (m, 2H,—CH₂—), 3.15 (m, 2H, —CH₂—), 4.15 (m, 2H, —CH₂—), 7.12 (d, 2H, Ar—H),7.80 (d, 2H, Ar—H) 40

111   1.744^(a) ¹H NMR (CDCl₃) 1.11 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.10 (d, 2H, Ar—H), 7.72 (d,2H, Ar—H) 41

180 9.784 CHPM ¹H NMR (CDCl₃) 1.09 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.20 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.05 (d, 1H, C—H), 7.32 (d,2H, Ar—H), 7.40 (d, 1H, C—H), 8.10 (d, 2H, Ar—H) 42

122   2.708^(a) ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 3.00 (m, 2H, —CH₂—),3.19 (m, 2H, —CH₂—), 4.10 (m, 2H, —CH₂—), 7.00 (d, 2H, Ar—H), 7.80 (d,2H, Ar—H)

Example 433-Chloro-6-{4-[(S)-2-methyl-3-((R)-2-methylpyrrolidin-1-yl)propoxy]-phenyl}pyridazine

(S)-2-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-propan-1-ol

(S)-3-Bromo-2-methylpropan-1-ol (6.2 g, 40 mmol) was dissolved in dryCH₃CN (100 mL) and dry, pulverized K₂CO₃ (10.4 g, 75 mmol) wasintroduced followed by4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (11.0 g, 50mmol). The reaction mixture was heated at 72° C. for 20 h, cooled andfiltered. The filtrate was evaporated to an oil, which was applied to acolumn of silica gel. Elution initially with hexanes, graduallyincreasing polarity to a mixture of hexanes/ethyl acetate (3:2) aseluent, provided the title compound (7.56 g, 64%) as an oil.

(S)-3-[4-(6-Chloro-pyridazin-3-yl)-phenoxy]-2-methyl-propan-1-ol

Pd(OAc)₂ trimer (0.84 g, 3.75 mmol) and Ph₃P (3.9 g, 15 mmol) weresuspended in anhydrous THF (200 mL) and stirred vigorously under anitrogen atmosphere for 10 min. 3,6-dichloropyridazine (8.94 g, 60 mmol)was added as a solid and stirring was continued for 45 min.

A solution of(S)-2-Methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propan-1-ol(4.38 g, 15 mmol) in a mixture of THF (50 mL) and EtOH (20 mL) was addeddropwise to the reaction mixture. Saturated NaHCO₃ solution (120 mL) wasintroduced. The reaction mixture was heated at 74° C. for 24 h, cooled,filtered and was evaporated to a residue, which was taken up in CH₂Cl₂(300 mL) and washed with water and saturated NaHCO₃ solution. The CH₂Cl₂phase was dried (Na₂SO₄) and evaporated. The title compound was obtainedby ISCO chromatography on silica gel, eluting with hexanes/EtOAc (9:1)initially, gradually increasing polarity to a 1:2 mixture of thesesolvents, to provide the title compound (3.22 g, 78%) as a white solid,m.p. 134-138° C.; ¹H NMR (CDCl₃) 1.10 (d, 3H, —CH₃), 2.22 (1H, m, C—H),3.72 (m, 2H, —CH₂—), 4.04 (m, 2H, —CH₂—), 7.04 (d, 2H, Ar—H), 7.51 (d,1H, C—H), 7.80 (d, 1H, C—H), 8.00 (d, 2H, Ar—H); HPLC retention time8.843 min. (elution solvents CH₃CN w/0.1% TFA and H₂O w/0.1% TFA);10-100% CH₃CN over 20 min.

3-Chloro-6-{4-[(S)-2-methyl-3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-pyridazine(Example 43)

(S)-3-[4-(6-Chloro-pyridazin-3-yl)phenoxy]-2-methylpropan-1-ol (3.0 g,10.76 mmol) was dissolved in a mixture of pyridine (10 mL) and THF (90mL), and the solution cooled to 0° C. Methanesulfonyl chloride (2.863 g,25 mmol) was introduced dropwise, and the reaction mixture was stirredat ambient temperature for 20 h. EtOAc (100 mL) and H₂O (150 mL) wereadded, separated, and the aqueous layer was extracted further with EtOAc(2×100 mL). The combined extracts were dried (MgSO₄) and evaporated to asolid which was purified by column chromatography on silica gel, elutingwith a gradient of hexane/EtOAc to provide the intermediatemethanesulfonic acid(R)-3-[4-(6-chloro-pyridazin-3-yl)-phenoxy]-2-methylpropyl ester (3.52g, 91%). This intermediate (7 mmol) was treated with(R)-2-methylpyrrolidine, benzenesulfonic acid salt (3.65 g, 15 mmol) anddry, pulverized K₂CO₃ (4.15 g, 30 mmol) in dry CH₃CN (200 mL). Thereaction mixture was heated at reflux for 30 h and cooled, filtered andthe filtrate evaporated. The residue was purified by columnchromatography, eluting with a gradient mixture of CH₂Cl₁₂ and EtOHcontaining 10% of aqueous ammonia solution, to provide the titlecompound (1.46 g, 60%), m.p. 152-155° C., ¹H NMR (CDCl₃) 1.18 (d, 3H,—CH₃), 1.27 (d, 3H, —CH₃), 3.98 (m, 2H, —CH₂—), 7.02 (d, 2H, Ar—H), 7.52(d, 1H, C—H), 7.78 (d, 1H, C—H), 8.02 (d, 2H, Ar—H); HPLC retention time7.530 min. (elution solvents CH₃CN w/0.1% TFA and H₂O w/0.1% TFA);10-100% CH₃CN over 20 min.

The following example was prepared by the procedure described in Example43.

TABLE III Melting HPLC Example Point Retention number Structure (° C.)Time (min.) NMR data 44

108-110 7.969 ¹H NMR (CDCl₃) 1.04 (d, 3H, —CH₃), 3.09 (m, 2H, —CH₂—),7.06 (d, 2H, Ar—H), 7.50 (d, 1H, C—H), 7.77 (d, 1H, C—H), 8.00 (d, 2H,Ar—H)

3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazineExample 456-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}pyridazine

(R)-2-Methyl-1-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]propyl}-pyrrolidine(1.1 g, 3.2 mmol), 3-chloropyridazine (0.485 g, 4.24 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.258 g, 0.223 mmol), K₂CO₃(1.19 g, 8.6 mmol) in 1,2-dimethoxyethane (25 mL) and water (11.5 mL)were combined and degassed with argon. The reaction was heated at 85° C.for 15 h, cooled to rt, filtered through celite, taken up in CH₂Cl₂ (30mL) and washed with water and saturated NaHCO₃ solution. The CH₂Cl₂layer was dried (Na₂SO₄) and evaporated. The product was purified byISCO chromatography on silica gel, eluting with 5-15% MeOH/DCM/0.5%NH₄OH. The HCl salt was prepared MeOH-ether-HCl to give a white solid,m.p. 198-201° C.; LCMS m/z=298 (M+1).

The compounds of the present invention are useful, inter alia, astherapeutic agents. Particularly, the compounds are useful forinteracting with the H₃ receptor. In one embodiment, the presentinvention provides a method for treating or preventing diseases anddisorders, such as those disclosed herein, which comprises administeringto a subject in need of such treatment or prevention a therapeuticallyeffective amount of a compound of the present invention.

In an additional embodiment, the present invention provides a method forinhibiting H₃ activity comprising providing a compound of the presentinvention in an amount sufficient to result in effective inhibition.Particularly, the compounds of the present invention can be administeredto treat such diseases and disorders such as narcolepsy or othersleep/wake disorders, such as obstructive sleep apnea/hypopnea syndrome,and shift work sleep disorder; feeding behavior, eating disorders,obesity, cognition, arousal, memory, mood disorders, mood attentionalteration, attention deficit hyperactivity disorder (ADHD), Alzheimer'sdisease/dementia, schizophrenia, pain, stress, migraine, motionsickness, depression, psychiatric disorders, epilepsy, gastrointestinaldisorders, respiratory disorders (such as asthma), inflammation, andmyocardial infarction. In certain embodiments, the compounds can beadministered to treat narcolepsy or other sleep/wake disorders, such asobstructive sleep apnea/hypopnea syndrome, and shift work sleepdisorder; obesity, cognition, attention deficit hyperactivity disorder(ADHD), and dementia. In other embodiments, the compounds can beadministered to treat narcolepsy or other sleep/wake disorders, such asobstructive sleep apnea/hypopnea syndrome, and shift work sleepdisorder; or they can used to treat obesity, or they can used to treatcognition, or they can used to treat attention deficit hyperactivitydisorder (ADHD), or they can used to treat dementia.

Compounds of the invention either have demonstrated or are expected todemonstrate inhibition of H₃ and thereby for utility for treatment ofthe indications described herein. Such utilities can be determinedusing, for example, the following assays as set forth below. They arenot intended, nor are they to be construed, as limiting the scope of thedisclosure.

Rat H₃ Assays:

Cell line development and membrane preparation. The rat H₃ receptor cDNAwas PCR amplified from reverse-transcribed RNA pooled from rat thalamus,hypothalamus, striatum and prefrontal cortex with a sequencecorresponding to by #338-1672 of Genbank file #NM_(—)053506, encodingthe entire 445-amino-acid rat histamine H₃ receptor. This was engineeredinto the pIRES-neo3 mammalian expression vector, which was stablytransfected into the CHO-A3 cell line (Euroscreen, Belgium), followed byclonal selection by limiting dilution. Cells were harvested and cellpellets were frozen (−80° C.). Cell pellets were resuspended in 5 mMTris-HCl, pH 7.5 with 5 nM EDTA and a cocktail of protease inhibitors(Complete Protease Inhibitor Tablets, Roche Diagnostics). Cells weredisrupted using a polytron cell homogenizer and the suspension wascentrifuged at 1000×g for 10 minutes at 4° C. The pellet was discardedand the supernatant centrifuged at 40,000×g for 30 min at 4° C. Thismembrane pellet was washed in membrane buffer containing 50 mM Tris-HCl,pH 7.5 with 0.6 mM EDTA, 5 mM MgCl₂ and protease inhibitors,recentrifuged as above and the final pellet resuspended in membranebuffer plus 250 mM sucrose and frozen at −80° C.

Radioligand Binding. Membranes were resuspended in 50 mM Tris HCl (pH7.4), 5 mM MgCl₂, 0.1% BSA. The membrane suspensions (10 μg protein perwell) were incubated in a 96 well microtiter plate with[³H]-N-alpha-methylhistamine (approximately 1 nM final concentration),test compounds at various concentrations (0.01 nM-30 μM) andscintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) in a final volume of 80 μl for 4 hours at room temperature,protected from light. Non-specific binding was determined in thepresence of 10 μM clobenpropit. Radioligand bound to receptor, andtherefore in proximity to the scintillation beads, was measured using aMicroBeta scintillation counter.

GTPγS Binding. Membranes were resuspended in 20 mM HEPES pH 7.4containing: 1 mM EDTA, 0.17 mg/ml dithiothreitol, 100 mM NaCl, 30 μg/mlsaponin and 5 mM MgCl₂. For measurement of inverse agonist activity,increasing concentrations of test compounds were incubated in a 96 wellmicrotiter plate with 10 μg/well membrane protein, 5 μM GDP,scintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) and [³⁵S]-GTPγS (0.1 nM final concentration). Followingincubation for 45 minutes in the dark at room temperature, themicrotiter plate was centrifuged at 1000×g for 5 minutes andradioactivity bound to the membranes was counted using a MicroBetascintillation counter. Non-specific binding was measured in the presenceof 10 μM GTP. A decrease in bound [³⁵S]-GTPγS is indicative of H₃receptor inverse agonist activity in this assay. Antagonist activity oftest compounds was determined in a similar experiment under thefollowing conditions. Membranes were resuspended in 20 mM HEPES pH 7.4containing: 1 mM EDTA, 0.17 mg/ml dithiothreitol, 200 mM NaCl, 30 μg/mlsaponin and 20 mM MgCl₂. The membranes were incubated at 10 μg/wellmembrane protein in a microtiter plate with increasing concentrations oftest compounds, 20 μM GDP, scintillation proximity beads and [³⁵S]-GTPγS(0.1 nM final concentration) plus 30 nM R-alpha-methylhistamine. Themicrotiter plates were incubated and processed as described above. Adecrease in R-alpha-methylhistamine stimulated [³⁵S]-GTPγS binding isindicative of H₃ receptor antagonist activity in this assay.

Human H₃ Assays:

Methods: CHO cells stably expressing the human H₃ receptor (GenBank:NM_(—)007232) were harvested and cell pellets were frozen (−80° C.).Cell pellets were resuspended in 5 mM Tris-HCl, pH 7.5 with 5 nM EDTAand a cocktail of protease inhibitors (Complete Protease InhibitorTablets, Roche Diagnostics). Cells were disrupted using a polytron cellhomogenizer and the suspension was centrifuged at 1000×g for 10 minutesat 4° C. The pellet was discarded and the supernatant centrifuged at40,000×g for 30 min at 4° C. This membrane pellet was washed in membranebuffer containing 50 mM Tris-HCl, pH 7.5 with 0.6 mM EDTA, 5 mM MgCl₂and protease inhibitors, recentrifuged as above and the final pelletresuspended in membrane buffer plus 250 mM sucrose and frozen at −80° C.

Radioligand Binding. Membranes were resuspended in 50 mM Tris HCl (pH7.4), 5 mM MgCl₂, 0.1% BSA. The membrane suspensions (10 μg protein perwell) were incubated in a 96 well microtiter plate with[³H]-N-alpha-methylhistamine (approximately 1 nM final concentration),test compounds at various concentrations (0.01 nM-30 μM) andscintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) in a final volume of 80 μl for 4 hours at room temperature,protected from light. Non-specific binding was determined in thepresence of 10 μM clobenpropit. Radioligand bound to receptor, andtherefore in proximity to the scintillation beads, was measured using aMicroBeta scintillation counter.

GTPγS Binding. Membranes were resuspended in 20 mM HEPES pH 7.4containing: 1 mM EDTA, 0.17 mg/ml dithiothreitol, 100 mM NaCl, 30 μg/mlsaponin and 5 mM MgCl₂. For measurement of inverse agonist activity,increasing concentrations of test compounds were incubated in a 96 wellmicrotiter plate with 10 μg/well membrane protein, 5 μM GDP,scintillation proximity beads (Perkin Elmer, FlashBlueGPCR ScintillatingBeads) and [³⁵S]-GTPγS (0.1 nM final concentration). Followingincubation for 45 minutes in the dark at room temperature, themicrotiter plate was centrifuged at 1000×g for 5 minutes andradioactivity bound to the membranes was counted using a MicroBetascintillation counter. Non-specific binding was measured in the presenceof 10 μM GTP. A decrease in bound [³⁵S]-GTPγS is indicative of H₃receptor inverse agonist activity in this assay. Antagonist activity oftest compounds was determined in a similar experiment under thefollowing conditions. Membranes were resuspended in 20 mM HEPES pH 7.4containing: 1 mM EDTA, 0.17 mg/ml dithiothreitol, 200 mM NaCl, 30 μg/mlsaponin and 20 mM MgCl₂. The membranes were incubated at 10 μg/wellmembrane protein in a microtiter plate with increasing concentrations oftest compounds, 20 μM GDP, scintillation proximity beads and [³⁵S]-GTPγS(0.1 nM final concentration) plus 30 nM R-alpha-methylhistamine. Themicrotiter plates were incubated and processed as described above. Adecrease in R-alpha-methylhistamine stimulated [³⁵S]-GTPγS binding isindicative of H₃ receptor antagonist activity in this assay.

Other assays that may be used in connection with the present inventionare set forth below. Examples of the present invention can be tested inthe following in vivo models:

Evaluation of Wake Promoting Activity in Rats

The methodology utilized for evaluating wake promoting activity of testcompounds is based on that described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997, andincorporated herein in its entirety by reference.

Compounds of the invention either have demonstrated or are expected todemonstrate utility for wake promoting activity.

Dipsogenia Model: Inhibition of histamine agonist-induced water drinkingin the rat. Histamine, and the H₃-selective agonist(R)-α-methylhistamine (RAMH) induce water drinking behavior in the ratwhen administered either peripherally or centrally (Kraly, F. S., June,K. R. 1982 Physiol. Behay. 28: 841; Leibowitz, S. F. 1973 Brain Res.63:440; Ligneau X., Lin, J-S., Vanni-Mercier G., Jouvet M., Muir J. L.,Ganellin C. R., Stark H., Elz S., Schunack W., Schwartz, J-C. 1998 JPharmcol. Exp. Ther. 287:658-66; Clapham, J. and Kilpatrick G. J. 1993Eur. J. Pharmacol. 232:99-103) an effect which is blocked by H₃ receptorantagonists thioperamide and ciproxifan. Compounds of the inventioneither have demonstrated or are expected to block RAMH induce waterdrinking behavior.Novel object discrimination: Novel object discrimination (NOD; alsoreferred to as novel object recognition) is an assay for short-termvisual recognition memory that was first described by Ennaceur andDelacour (Ennaceur, A. and Delacour, J. (1988) Behav Brain Res 31:47-59).Social recognition: Social recognition (SR) is an assay for short-termsocial (olfactory) memory that was first described by Thor and Holloway(1982). Thor, D. and Holloway, W. (1982) J Comp Physiolog Psychcol 96:1000-1006.

Compounds of the invention either have demonstrated or are expected todemonstrate inhibition of H₃ and thereby utility for treatment of theindications described herein.

Table B lists the Human binding data for Examples 1-45 of the presentinvention. Binding constants (K_(i)) for Examples 1-45 in the Human H₃method described herein are expressed by letter descriptor to indicatethe following ranges: “+++” is less than 50 nM; “++” is 51-100 nM; “+”is >101 nM.

TABLE B EXAMPLE NUMBER HUMAN H₃ BINDING K_(i) (nM) 1 +++ 2 +++ 3 +++ 4+++ 5 +++ 6 +++ 7 +++ 8 +++ 9 +++ 10 + 11 + 12 +++ 13 +++ 14 + 15 +++ 16+++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26+++ 27 +++ 28 +++ 29 +++ 30 +++ 31 ++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++37 +++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 + 45 +++

It should be understood that while this invention has been describedherein in terms of specific embodiments set forth in detail, suchembodiments are presented by way of illustration of the generalprinciples of the invention, and the invention is not necessarilylimited thereto. Certain modifications and variations in any givenmaterial, process step or chemical formula will be readily apparent tothose skilled in the art without departing from the true spirit andscope of the present invention, and all such modifications andvariations should be considered within the scope of the claims thatfollow.

What is claimed:
 1. A method for alleviating a symptom of a disease ordisorder which is narcolepsy, a sleep/wake disorder, a cognitiondisorder, a memory disorder, attention deficit hyperactivity disorder(ADHD), Alzheimer's disease or dementia, comprising administering to apatient afflicted with the disease or disorder a therapeuticallyeffective amount of a compound of Formula I:

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: R¹ is H, —OR⁷, —SR⁷, —SOR⁷, —SO₂R⁷, —NR⁹R¹⁰, halogen, C₁₋₄alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂ aryl, 5-10 memberedheteroaryl, or 3-10 membered heterocycloalkyl, wherein each of said C₁₋₄alkyl, C₄₋₁₀ cycloalkyl, C₁₋₄ haloalkyl, C₆₋₁₂ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocycloalkyl is optionally substitutedby 1, 2, or 3 R¹¹; R² and R³ are independently H or C₁₋₄ alkyl; or R²and R³ are taken together to form a C₄₋₁₀ cycloalkyl or phenyl, whereineach of said C₄₋₁₀ cycloalkyl and phenyl is optionally substituted by 1,2, or 3 halogen or C₁₋₄ alkyl; each R⁴ is independently H or C₁₋₄ alkylor OH; each R⁵ is independently C₁₋₄ alkyl, or hydroxyalkyl; each R⁶ isindependently halogen, C₁₋₄ haloalkyl, —OH, C₁₋₄ alkyl, —O—C₁₋₄ alkyl,—NR⁹R¹⁰, or CN; R⁷ is C₁₋₄ alkyl, C₄₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, C₆₋₁₂ aryl, C₆₋₁₂ arylC₁₋₆alkyl, 5-10 memberedheteroarylalkyl, or a 3-10 membered heterocycloalkyl; R⁹ and R¹⁰ areindependently H, C₁₋₄ alkyl, or arylalkyl; each R¹¹ is halogen, —OH,—OC₁₋₄ alkyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or —CN; X is O or S; m is 2,3, 4, 5, or 6; n is 0, 1, or 2; y is 0, 1, 2, 3, or 4; and z is 0, 1, 2,3, or
 4. 2. A method according to claim 1, wherein in the compound R¹ ishalogen, C₁₋₄ alkyl, aryl, heteroaryl, heterocycloalkyl, or —NR⁹R¹⁰. 3.A method according to claim 1, wherein in the compound R¹ is H, halogen,or —NH₂.
 4. A compound according to claim 1, wherein in the compound R¹is OR⁷.
 5. A method according to claim 1, wherein in the compound R¹ is—SR⁷, —SOR⁷, or —SO₂R⁷.
 6. A method according to claim 1, wherein in thecompound R¹ is H, methyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, benzylsulfanyl, pyridinyl, —OC₁₋₄alkyl, —Oaryl, —OCH₂aryl,—SC₁₋₄alkyl, —SCH₂aryl, —SOCH₂aryl, —SO₂CH₂aryl, or benzofuranyl.
 7. Amethod according to claim 1, wherein in the compound R⁵ is C₁₋₄ alkyland n is
 0. 8. A method according to claim 1, wherein in the compoundR², R³, R⁴ and R⁶ are each H.
 9. A method according to claim 1, whereinin the compound R² and R³ are taken together to form a C₄₋₁₀ cycloalkyl.10. A method according to claim 1, wherein in the compound R² and R³ aretaken together to form a phenyl.
 11. A method according to claim 1,wherein in the compound each R⁴ is independently H or methyl.
 12. Amethod according to claim 1, wherein in the compound each R⁵ is methyl.13. A method according to claim 1, wherein in the compound each R⁶ isindependently C₁₋₄alkyl.
 14. A method according to claim 1, wherein inthe compound m is 2 or
 3. 15. A method according to claim 1, wherein inthe compound n is 0 or
 1. 16. A method according to claim 1, wherein inthe compound y is
 0. 17. A method according to claim 1, wherein in thecompound z is
 1. 18. A method according to claim 1, wherein in thecompound X is
 0. 19. A method according to claim 1, wherein the compoundof Formula I is selected from the group consisting of:3-Chloro-6-{4-[3-((R)-2-methylpyrrolidin1-yl)propoxy]phenyl}pyridazine;3-Chloro-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]pyridazine;3-Methyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenylpyridazine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-pyrrolidin-1-yl-pyridazine;4-(6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)morpholine;6-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazin-3-ylamine;Methyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)amine;1-(6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazin-3-yl)piperidin-4-ol;3-Chloro-6-{3-methoxy-4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy}phenyl}pyridazine;3-Chloro-6-[3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;3-Chloro-6-[2-methyl-4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;5-(6-Chloro-pyridazin-3-yl)-2-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]benzonitrile;5-(6-Chloro-pyridazin-3-yl)-2-(3-piperidin-1-yl-propoxy)benzonitrile;1-Chloro-4-[4-(3-piperidin-1-yl-propoxy)-phenyl]-6,7-dihydro-5H-cyclopenta[d]pyridazine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]phenyl}-6-thiophen-2-yl-pyridazine;1-Chloro-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6,7-dihydro-5H-cyclopenta[d]pyridazine;3-Chloro-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-diaza-tricyclo[6.2.2.0*2,7*]dodeca-2(7),3,5-triene;3-(5-Chloro-pyridin-3-yloxy)-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxyphenyl}pyridazine;3-Benzyloxy-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;3-Benzyloxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;3-Methoxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl-propoxy]-phenyl}pyridazine;3-Methoxy-6-{4-3-piperidin-1-yl-propoxy)-phenyl]pyridazine;3-Isopropoxy-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenylpyridazine;3-Phenoxy-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;3-(4-Fluoro-benzyloxy)-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-(4-trifluoromethyl-benzyloxy)pyridazine;Ethyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazin-3-yl)amine;Benzyl-(6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazin-3-yl)amine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl-propoxy]-phenyl}-6-methylsulfanylpyridazine;3-Methylsulfanyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;1-{4-[3-((R)-2-Methyl-pyrrolodin-1-yl)-propoxy]-phenyl}-4-methylsulfanyl-6,7-dihydro-5H-cyclopenta[d]pyridazine;3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]phenyl}pyridazine;3-Benzylsulfanyl-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]pyridazine;3-{4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-phenylmethanesulfinyl-pyridazine;3-Phenylmethanesulfinyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;3-(4-[3-((R)-2-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl)-6-phenylmethanesulfinyl-pyridazine;3-Phenylmethanesulfinyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]pyridazine;1-Methoxy-4-{4-[3-((R)-2-methylpyrrolidin-1-yl)-propoxy]-phenyl}6,7-dihydro-5H-cyclopenta[d]pyridazine;1-Methoxy-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl-propoxy]-phenyl}phthalazine;3-Benzofuran-2-yl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}pyridazine;1-Benzylsulfanyl-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]-phenyl}-6,7-dihydro-5H-cyclopenta[d]pyridazine;3-Chloro-6-{4-[(S)-2-methyl-3-((R)-2-methylpyrrolidin-1-yl)-propoxy]phenyl}pyridazine;3-Chloro-6-{4-[(S)-2-methyl-3-(2-methylpiperidin-1-yl)propoxy]-phenyl}pyridazine;and 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)propoxy]phenyl}pyridazine; ora stereoisomer or a pharmaceutically acceptable salt thereof.
 20. Amethod according to claim 1, wherein the disease or disorder isnarcolepsy.
 21. A method according to claim 1, wherein the disease ordisorder is attention deficit hyperactivity disorder.
 22. A methodaccording to claim 1, wherein the disorder is a cognition disorder. 23.A method according to claim 1, wherein the disorder is a sleep/wakedisorder which is obstructive sleep apnea/hypopnea syndrome, or shiftwork sleep disorder.